The cell cycle is an ordered set of events, culminating in cell growth and division into two daughter cells. It consists of four distinct stages: gap number 1 (G1); synthesis (S); gap number 2 (G2) and mitosis or cell division (M). Control of the cell cycle is very complex and involves regulation at a number of levels. Cell cycle checkpoints are regulatory pathways that control the order and timing of cell cycle transitions and ensure that critical events such as DNA replication and chromosome segregation are completed correctly before letting the cell progress further through the cycle.
In cancerous cells, the normal regulatory processes are disrupted and cell growth is uncontrolled. One of the main abnormalities in human cancer cells is the loss of the G1 phase checkpoint, primarily due to mutations in p53. Consequently, enforcement of the G2/M checkpoint represents an attractive mode of action for new antineoplastic agents, as sustained arrest of cancer cells in G2/M phase triggers cell death by apoptosis.
G2/M progression is tightly regulated by several cellular macromolecules, including tubulins, microtubule-associated proteins and motor proteins, such as kinesins and dynesins. Targeting the G2/M checkpoint has been clinically validated with drugs that either stabilize (taxanes) or disrupt (vinca alkaloids) microtubule formation. In addition, the importance of G2/M arrest was also validated in the clinic with drugs that have different molecular targets, e.g., Velcade (proteasome inhibitor).
We describe here a new class of water-soluble, highly potent compounds that are able to arrest tumor cells in G2/M phase but producing gene expression profile different from known antimitotic agents. It is possible that treatment of solid tumor cancers with such drugs may lead to higher anticancer efficacy and reduced toxic side effects typical for antimitotic agents. These compounds are derived from 1-(substituted sulfonyl)-2-aminoimidazoline. Structurally related 1-sulphanilyl-2-imino-imidazolidine derivatives have been reported as anti-glycemic agents (see, for example, GB Patent No. 1174152), and arylsulfonylimidazolone derivatives were disclosed as antineoplastic agents, with activity superior to the known antitumor sulfonylureas (U.S. Pat. No. 5,932,742). However, those compounds are not soluble in water, which is a serious disadvantage for cytotoxic anticancer agents that commonly are administered in highly controlled manner as slow iv injections.